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Oral tolerance to copolymer 1 in myelin basic protein (MBP) TCR transgenic mice: cross-reactivity with MBP-specific TCR and differential induction of anti-inflammatory cytokines.
Int Immunol 2002; 14(2):131-8II

Abstract

Oral tolerance to myelin basic protein (MBP) is an effective antigen-specific method to suppress experimental allergic encephalomyelitis (EAE). Glatiramer acetate [copolymer 1 (Cop1)] is a synthetic copolymer designed to mimic MBP which suppresses EAE, is used parenterally to treat multiple sclerosis (MS) and is being tested orally for efficacy in MS. We investigated the immunologic properties of Cop1 to determine the degree to which its effects were antigen specific using MBP TCR transgenic mice. Immunization of MBP TCR transgenic mice fed Cop1, MBP or MBP Ac1-11 resulted in decreased proliferation, and IL-2, IL-6 and IFN-gamma production, and increased secretion of IL-10 and transforming growth factor (TGF)-beta in Cop1-fed animals. IFN-gamma was decreased, and IL-10 and TGF-beta were increased in non-immunized mice fed Cop1 and stimulated in vitro with MBP. No such effects were observed in ovalbumin TCR transgenic mice. To determine if the effects of Cop1 were specific to MBP TCR-bearing cells, MBP TCR transgenic Rag2(-/-) mice were immunized and re-stimulated in vitro with Cop1. We found a marked increase in IL-4 and similar increases in IL-4 after feeding Cop1. In disease models, feeding Cop1 suppressed EAE in MBP TCR transgenic mice, (PL/J x SJL)F(1) mice, and in myelin oligodendrocyte glycoprotein-induced EAE in NOD mice. Oral Cop1 had no effect on collagen-induced arthritis. These results demonstrate that Cop1 is active orally in an antigen-specific fashion, and may function as an altered peptide ligand for MBP-specific TCR-bearing cells by decreasing pro-inflammatory cytokines (IFN-gamma) and increasing anti-inflammatory cytokines (IL-4, IL-10 and TGF-beta).

Authors+Show Affiliations

Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11809732

Citation

Maron, Ruth, et al. "Oral Tolerance to Copolymer 1 in Myelin Basic Protein (MBP) TCR Transgenic Mice: Cross-reactivity With MBP-specific TCR and Differential Induction of Anti-inflammatory Cytokines." International Immunology, vol. 14, no. 2, 2002, pp. 131-8.
Maron R, Slavin AJ, Hoffmann E, et al. Oral tolerance to copolymer 1 in myelin basic protein (MBP) TCR transgenic mice: cross-reactivity with MBP-specific TCR and differential induction of anti-inflammatory cytokines. Int Immunol. 2002;14(2):131-8.
Maron, R., Slavin, A. J., Hoffmann, E., Komagata, Y., & Weiner, H. L. (2002). Oral tolerance to copolymer 1 in myelin basic protein (MBP) TCR transgenic mice: cross-reactivity with MBP-specific TCR and differential induction of anti-inflammatory cytokines. International Immunology, 14(2), pp. 131-8.
Maron R, et al. Oral Tolerance to Copolymer 1 in Myelin Basic Protein (MBP) TCR Transgenic Mice: Cross-reactivity With MBP-specific TCR and Differential Induction of Anti-inflammatory Cytokines. Int Immunol. 2002;14(2):131-8. PubMed PMID: 11809732.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oral tolerance to copolymer 1 in myelin basic protein (MBP) TCR transgenic mice: cross-reactivity with MBP-specific TCR and differential induction of anti-inflammatory cytokines. AU - Maron,Ruth, AU - Slavin,Anthony J, AU - Hoffmann,Ethan, AU - Komagata,Yoshinori, AU - Weiner,Howard L, PY - 2002/1/26/pubmed PY - 2002/5/3/medline PY - 2002/1/26/entrez SP - 131 EP - 8 JF - International immunology JO - Int. Immunol. VL - 14 IS - 2 N2 - Oral tolerance to myelin basic protein (MBP) is an effective antigen-specific method to suppress experimental allergic encephalomyelitis (EAE). Glatiramer acetate [copolymer 1 (Cop1)] is a synthetic copolymer designed to mimic MBP which suppresses EAE, is used parenterally to treat multiple sclerosis (MS) and is being tested orally for efficacy in MS. We investigated the immunologic properties of Cop1 to determine the degree to which its effects were antigen specific using MBP TCR transgenic mice. Immunization of MBP TCR transgenic mice fed Cop1, MBP or MBP Ac1-11 resulted in decreased proliferation, and IL-2, IL-6 and IFN-gamma production, and increased secretion of IL-10 and transforming growth factor (TGF)-beta in Cop1-fed animals. IFN-gamma was decreased, and IL-10 and TGF-beta were increased in non-immunized mice fed Cop1 and stimulated in vitro with MBP. No such effects were observed in ovalbumin TCR transgenic mice. To determine if the effects of Cop1 were specific to MBP TCR-bearing cells, MBP TCR transgenic Rag2(-/-) mice were immunized and re-stimulated in vitro with Cop1. We found a marked increase in IL-4 and similar increases in IL-4 after feeding Cop1. In disease models, feeding Cop1 suppressed EAE in MBP TCR transgenic mice, (PL/J x SJL)F(1) mice, and in myelin oligodendrocyte glycoprotein-induced EAE in NOD mice. Oral Cop1 had no effect on collagen-induced arthritis. These results demonstrate that Cop1 is active orally in an antigen-specific fashion, and may function as an altered peptide ligand for MBP-specific TCR-bearing cells by decreasing pro-inflammatory cytokines (IFN-gamma) and increasing anti-inflammatory cytokines (IL-4, IL-10 and TGF-beta). SN - 0953-8178 UR - https://www.unboundmedicine.com/medline/citation/11809732/Oral_tolerance_to_copolymer_1_in_myelin_basic_protein__MBP__TCR_transgenic_mice:_cross_reactivity_with_MBP_specific_TCR_and_differential_induction_of_anti_inflammatory_cytokines_ L2 - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=linkout&SEARCH=11809732.ui DB - PRIME DP - Unbound Medicine ER -